Cyclo phosphamide treatment during the pre implantation period 2. in vitro studies on the effects of cyclo phosphamide and its metabolites 4 hydroxy cyclo phosphamide phosphoramide mustard and acrolein on blastulation of 4 cell and 8 cell mouse embryos and on their subsequent development during implantation

Spielmann, H.; Jacob-Mueller, U.

Teratology 23(1): 7-14


ISSN/ISBN: 0040-3709
Accession: 005079605

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Preimplantation mouse embryos were cultured for 48 h from the 4 cell and 8 cell stage to the blastocyst stage in the presence of cyclophosphamide (CPA) or 1 of its metabolites.sbd.4-hydroperoxy-CPA (4-HP-CPA), phosphoramide mustard (PAM) and acrolein (Acr) identify the metabolite which is embryotoxic after CPA treatment of pregnant mice during the preimplantation period. The dose-response relations for the inhibition of blastulation revealed identical inhibition curves for PAM and 4-HP-CPA (in solution 4-HP-CPA immediately decomposes to 4-hydroxy-CPA (4-OH-CPA)). These 2 metabolites are inhibiting blastulation in vitro at concentrations that are 10,000 times lower than CPA and 100 times lower than acrolein. When blastocysts which developed in the presence of CPA and its metabolites in vitro were subsequently cultured in inhibitor-free medium NCTC-109, the same dose-response relationship pattern was obtained. Since 4-OH-CPA decomposes into acrolein and PAM in vivo and in vitro and since PAM and 4-OH-CPA exhibit identical embryotoxicity towards preimplantation embryos in vitro, PAM probably also is an active embryotoxic CPA metabolite in vivo before implantation. This result is discussed in relation to the importance of alkylating CPA metab olites in cancer treatment and in teratological studies during organogenesis.